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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2014

Open Access 01-12-2014 | Research article

Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase

Authors: Virginie Buggia-Prévot, Celia G Fernandez, Sean Riordan, Kulandaivelu S Vetrivel, Jelita Roseman, Jack Waters, Vytautas P Bindokas, Robert Vassar, Gopal Thinakaran

Published in: Molecular Neurodegeneration | Issue 1/2014

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Abstract

Background

BACE1 is one of the two enzymes that cleave amyloid precursor protein to generate Alzheimer's disease (AD) beta amyloid peptides. It is widely believed that BACE1 initiates APP processing in endosomes, and in the brain this cleavage is known to occur during axonal transport of APP. In addition, BACE1 accumulates in dystrophic neurites surrounding brain senile plaques in individuals with AD, suggesting that abnormal accumulation of BACE1 at presynaptic terminals contributes to pathogenesis in AD. However, only limited information is available on BACE1 axonal transport and targeting.

Results

By visualizing BACE1-YFP dynamics using live imaging, we demonstrate that BACE1 undergoes bi-directional transport in dynamic tubulo-vesicular carriers along axons in cultured hippocampal neurons and in acute hippocampal slices of transgenic mice. In addition, a subset of BACE1 is present in larger stationary structures, which are active presynaptic sites. In cultured neurons, BACE1-YFP is preferentially targeted to axons over time, consistent with predominant in vivo localization of BACE1 in presynaptic terminals. Confocal analysis and dual-color live imaging revealed a localization and dynamic transport of BACE1 along dendrites and axons in Rab11-positive recycling endosomes. Impairment of Rab11 function leads to a diminution of total and endocytosed BACE1 in axons, concomitant with an increase in the soma. Together, these results suggest that BACE1 is sorted to axons in endosomes in a Rab11-dependent manner.

Conclusion

Our results reveal novel information on dynamic BACE1 transport in neurons, and demonstrate that Rab11-GTPase function is critical for axonal sorting of BACE1. Thus, we suggest that BACE1 transcytosis in endosomes contributes to presynaptic BACE1 localization.
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Literature
1.
Vassar R, et al: Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999, 286 (5440): 735-741. 10.1126/science.286.5440.735.CrossRefPubMed
2.
Sinha S, et al: Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999, 402 (6761): 537-540. 10.1038/990114.CrossRefPubMed
3.
Yan R, et al: Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999, 402 (6761): 533-537. 10.1038/990107.CrossRefPubMed
4.
Hussain I, et al: Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci. 1999, 14 (6): 419-427. 10.1006/mcne.1999.0811.CrossRefPubMed
5.
Lin X, et al: Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000, 97 (4): 1456-1460. 10.1073/pnas.97.4.1456.PubMedCentralCrossRefPubMed
6.
Thinakaran G, Koo EH: Amyloid precursor protein trafficking, processing, and function. J Biol Chem. 2008, 283 (44): 29615-29619. 10.1074/jbc.R800019200.PubMedCentralCrossRefPubMed
7.
Mullan M, et al: A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992, 1 (5): 345-347. 10.1038/ng0892-345.CrossRefPubMed
8.
Citron M, et al: Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature. 1992, 360 (6405): 672-674. 10.1038/360672a0.CrossRefPubMed
9.
Cai XD, Golde TE, Younkin SG: Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science. 1993, 259 (5094): 514-516. 10.1126/science.8424174.CrossRefPubMed
10.
Jonsson T, et al: A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012, 48: 96-99.CrossRef
11.
Rajendran L, Annaert W: Membrane Trafficking Pathways in Alzheimer's Disease. Traffic. 2012, 13 (6): 759-770. 10.1111/j.1600-0854.2012.01332.x.CrossRefPubMed
12.
Haass C, et al: Trafficking and proteolytic processing of APP. The biology of Alzheimer disease. Edited by: Selkoe DJ, Mandelkow E, Holtzman DM. 2012, Cold spring harbor, New York: Cold spring harbor laboratory press, 205-229.
13.
Huse JT, et al: Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease beta-secretase. J Biol Chem. 2000, 275 (43): 33729-33737. 10.1074/jbc.M004175200.CrossRefPubMed
14.
Chia PZ, et al: Intracellular Itinerary of Internalised beta-Secretase, BACE1, and Its Potential Impact on beta-Amyloid Peptide Biogenesis. Traffic. 2013, 14 (9): 997-1013. 10.1111/tra.12088.CrossRefPubMed
15.
He X, et al: GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J Biol Chem. 2005, 280 (12): 11696-11703. 10.1074/jbc.M411296200.CrossRefPubMed
16.
Wahle T, et al: GGA1 is expressed in the human brain and affects the generation of amyloid beta-peptide. J Neurosci. 2006, 26 (49): 12838-12846. 10.1523/JNEUROSCI.1982-06.2006.CrossRefPubMed
17.
18.
Rajendran L, et al: Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting. Science. 2008, 320 (5875): 520-523. 10.1126/science.1156609.CrossRefPubMed
19.
Cirrito JR, et al: Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005, 48 (6): 913-922. 10.1016/j.neuron.2005.10.028.CrossRefPubMed
20.
Cirrito JR, et al: Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008, 58 (1): 42-51. 10.1016/j.neuron.2008.02.003.PubMedCentralCrossRefPubMed
21.
Das U, et al: Activity-Induced Convergence of APP and BACE-1 in Acidic Microdomains via an Endocytosis-Dependent Pathway. Neuron. 2013, 79 (3): 447-460. 10.1016/j.neuron.2013.05.035.PubMedCentralCrossRefPubMed
22.
Lasiecka ZM, Winckler B: Mechanisms of polarized membrane trafficking in neurons - Focusing in on endosomes. Mol Cell Neurosci. 2011, 48 (4): 278-287. 10.1016/j.mcn.2011.06.013.PubMedCentralCrossRefPubMed
23.
Buxbaum JD, et al: Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path. J Neurosci. 1998, 18 (23): 9629-9637.PubMed
24.
Lazarov O, et al: Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci. 2002, 22 (22): 9785-9793.PubMed
25.
Sheng JG, Price DL, Koliatsos VE: Disruption of corticocortical connections ameliorates amyloid burden in terminal fields in a transgenic model of Abeta amyloidosis. J Neurosci. 2002, 22 (22): 9794-9799.PubMed
26.
Harris JA, et al: Transsynaptic progression of amyloid-beta-induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron. 2010, 68 (3): 428-441. 10.1016/j.neuron.2010.10.020.PubMedCentralCrossRefPubMed
27.
Sokolow S, et al: Preferential accumulation of amyloid-beta in presynaptic glutamatergic terminals (VGluT1 and VGluT2) in Alzheimer's disease cortex. Neurobiol Dis. 2012, 45 (1): 381-387. 10.1016/j.nbd.2011.08.027.PubMedCentralCrossRefPubMed
28.
Laird FM, et al: BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci. 2005, 25 (50): 11693-11709. 10.1523/JNEUROSCI.2766-05.2005.PubMedCentralCrossRefPubMed
29.
Goldsbury C, et al: Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta peptides. Traffic. 2006, 7 (7): 873-888. 10.1111/j.1600-0854.2006.00434.x.CrossRefPubMed
30.
Zhao J, et al: Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci. 2007, 27 (14): 3639-3649. 10.1523/JNEUROSCI.4396-06.2007.CrossRefPubMed
31.
Sannerud R, et al: ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. Proc Natl Acad Sci U S A. 2011, 108 (34): E559-E568. 10.1073/pnas.1100745108.PubMedCentralCrossRefPubMed
32.
Deng M, et al: Increased Expression of Reticulon 3 in Neurons Leads to Reduced Axonal Transport of beta Site Amyloid Precursor Protein-cleaving Enzyme 1. J Biol Chem. 2013, 288 (42): 30236-30245. 10.1074/jbc.M113.480079.PubMedCentralCrossRefPubMed
33.
Kandalepas PC, et al: The Alzheimer's beta-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol. 2013, 126 (3): 329-352. 10.1007/s00401-013-1152-3.PubMedCentralCrossRefPubMed
34.
Buggia-Prévot V, et al: A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease Aβ production. Cell Rep. 2013, 5 (6): 1552-1563. 10.1016/j.celrep.2013.12.006.PubMedCentralCrossRefPubMed
35.
Wu J, et al: Arc/Arg3.1 Regulates an Endosomal Pathway Essential for Activity-Dependent beta-Amyloid Generation. Cell. 2011, 147 (3): 615-628. 10.1016/j.cell.2011.09.036.PubMedCentralCrossRefPubMed
36.
37.
Prekeris R, Foletti DL, Scheller RH: Dynamics of tubulovesicular recycling endosomes in hippocampal neurons. J Neurosci. 1999, 19 (23): 10324-10337.PubMed
38.
Balaji J, Ryan TA: Single-vesicle imaging reveals that synaptic vesicle exocytosis and endocytosis are coupled by a single stochastic mode. Proc Natl Acad Sci U S A. 2007, 104 (51): 20576-20581. 10.1073/pnas.0707574105.PubMedCentralCrossRefPubMed
39.
Sonnichsen B, et al: Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rab11. J Cell Biol. 2000, 149 (4): 901-914. 10.1083/jcb.149.4.901.PubMedCentralCrossRefPubMed
40.
Park M, et al: Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron. 2006, 52 (5): 817-830. 10.1016/j.neuron.2006.09.040.PubMedCentralCrossRefPubMed
41.
Ascano M, et al: Axonal targeting of Trk receptors via transcytosis regulates sensitivity to neurotrophin responses. J Neurosci. 2009, 29 (37): 11674-11685. 10.1523/JNEUROSCI.1542-09.2009.PubMedCentralCrossRefPubMed
42.
Kawauchi T, et al: Rab GTPases-dependent endocytic pathways regulate neuronal migration and maturation through N-cadherin trafficking. Neuron. 2010, 67 (4): 588-602. 10.1016/j.neuron.2010.07.007.CrossRefPubMed
43.
Sekine-Aizawa Y, Huganir RL: Imaging of receptor trafficking by using alpha-bungarotoxin-binding-site-tagged receptors. Proc Natl Acad Sci U S A. 2004, 101 (49): 17114-17119. 10.1073/pnas.0407563101.PubMedCentralCrossRefPubMed
44.
Darstein M, et al: Distribution of kainate receptor subunits at hippocampal mossy fiber synapses. J Neurosci. 2003, 23 (22): 8013-8019.PubMed
45.
Huyghe D, et al: Endocytosis of the glutamate receptor subunit GluK3 controls polarized trafficking. J Neurosci. 2011, 31 (32): 11645-11654. 10.1523/JNEUROSCI.2206-11.2011.CrossRefPubMed
46.
Martin S, et al: Bidirectional regulation of kainate receptor surface expression in hippocampal neurons. J Biol Chem. 2008, 283 (52): 36435-36440. 10.1074/jbc.M806447200.PubMedCentralCrossRefPubMed
47.
Kuhn PH, et al: Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 2012, 31 (14): 3157-3168. 10.1038/emboj.2012.173.PubMedCentralCrossRefPubMed
48.
Zhou L, et al: The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J Biol Chem. 2012, 287 (31): 25927-25940. 10.1074/jbc.M112.377465.PubMedCentralCrossRefPubMed
49.
Yap CC, et al: The somatodendritic endosomal regulator NEEP21 facilitates axonal targeting of L1/NgCAM. J Cell Biol. 2008, 180 (4): 827-842. 10.1083/jcb.200707143.PubMedCentralCrossRefPubMed
50.
Bel C, et al: Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis. J Cell Sci. 2009, 122 (Pt 18): 3403-3413.CrossRefPubMed
51.
Udayar V, et al: A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of β-amyloid production. Cell Rep. 2013, 5 (6): 1536-1551. 10.1016/j.celrep.2013.12.005.PubMedCentralCrossRefPubMed
52.
Li X, et al: Aberrant Rab11-dependent trafficking of the neuronal glutamate transporter EAAC1 causes oxidative stress and cell death in Huntington's disease. J Neurosci. 2010, 30 (13): 4552-4561. 10.1523/JNEUROSCI.5865-09.2010.PubMedCentralCrossRefPubMed
53.
Ren M, et al: Hydrolysis of GTP on rab11 is required for the direct delivery of transferrin from the pericentriolar recycling compartment to the cell surface but not from sorting endosomes. Proc Natl Acad Sci U S A. 1998, 95 (11): 6187-6192. 10.1073/pnas.95.11.6187.PubMedCentralCrossRefPubMed
54.
Gossen M, Bujard H: Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A. 1992, 89 (12): 5547-5551. 10.1073/pnas.89.12.5547.PubMedCentralCrossRefPubMed
55.
56.
Gong P, et al: Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice. Mol Neurodegener. 2011, 6: 87-10.1186/1750-1326-6-87.PubMedCentralCrossRefPubMed
57.
Kaech S, Banker G: Culturing hippocampal neurons. Nat Protoc. 2006, 1 (5): 2406-2415. 10.1038/nprot.2006.356.CrossRefPubMed
58.
Ryan TA, et al: The kinetics of synaptic vesicle recycling measured at single presynaptic boutons. Neuron. 1993, 11 (4): 713-724. 10.1016/0896-6273(93)90081-2.CrossRefPubMed
59.
Forster B, et al: Complex wavelets for extended depth-of-field: a new method for the fusion of multichannel microscopy images. Microsc Res Tech. 2004, 65 (1–2): 33-42.CrossRefPubMed
60.
61.
Sampo B, et al: Two distinct mechanisms target membrane proteins to the axonal surface. Neuron. 2003, 37 (4): 611-624. 10.1016/S0896-6273(03)00058-8.CrossRefPubMed
62.
Bolte S, Cordelieres FP: A guided tour into subcellular colocalization analysis in light microscopy. J Microsc. 2006, 224 (Pt 3): 213-232.CrossRefPubMed
Metadata
Title
Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase
Authors
Virginie Buggia-Prévot
Celia G Fernandez
Sean Riordan
Kulandaivelu S Vetrivel
Jelita Roseman
Jack Waters
Vytautas P Bindokas
Robert Vassar
Gopal Thinakaran
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2014
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-9-1

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